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Structural Basis of Dot1L Stimulation by Histone H2B Lysine 120 Ubiquitination

Structural Basis of Dot1L Stimulation by Histone H2B Lysine 120 Ubiquitination

Marco Igor Valencia-Sánchez, Pablo De Ioannes, Miao Wang, Nikita Vasilyev, Ruoyu Chen, Evgeny Nudler, Jean-Paul Armache, Karim-Jean Armache

Mol Cell. 2019 Jun 6;74(5):1010-1019.e6.

PMID: 30981630

Abstract:

The essential histone H3 lysine 79 methyltransferase Dot1L regulates transcription and genomic stability and is deregulated in leukemia. The activity of Dot1L is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120Ub); however, the detailed mechanism is not understood. We report cryo-EM structures of human Dot1L bound to (1) H2BK120Ub and (2) unmodified nucleosome substrates at 3.5 Å and 4.9 Å, respectively. Comparison of both structures, complemented with biochemical experiments, provides critical insights into the mechanism of Dot1L stimulation by H2BK120Ub. Both structures show Dot1L binding to the same extended surface of the histone octamer. In yeast, this surface is used by silencing proteins involved in heterochromatin formation, explaining the mechanism of their competition with Dot1. These results provide a strong foundation for understanding conserved crosstalk between histone modifications found at actively transcribed genes and offer a general model of how ubiquitin might regulate the activity of chromatin enzymes.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416071	Dot1L human			Price
IAR4246408	Histone H2B human			Price

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